Fig. 4 Sagittal (side view) of the brain and head (illustration)
Fig. 3 Chronic Stroke (illustration)
Fig. 2 Fluorescence photomontage
Fig. 6 Intracranial Treatment Behavior results (graph)
Fig. 7 Intranasal Treatment Behavior results (graph)
Fig. 9 Pre-migration
Fig. 10 Migration

Sagittal (side) view of the brain and head (inset at right) illustrating intracranially or intranasally infused TGFα into the brain containing a chronic stroke.

Using both application methods, the TGFa is able to diffuse and reach the ependymal and subependymal zones of the brain to stimulate “quiet” adult stem cells and induce them to divide into massive numbers of new progenitor cells which migrate to zones of damage in the brain, in this case, chronic stroke.

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Cross section of the brain (similar to Fig 01) illustrating how TGFα acts to repair damage in the brain of patients (and animal models) with chronic stroke.

At the right are the key brain structures involved, including the striatum, the pallidum, the thalamus, and the midbrain dopamine neurons of the substantia nigra-ventral tegmental area. At left the cortical-striatal pallidal-nigral-thalamic-cortical “loop” is shown. In chronic stroke, all the neurons in the central (umbra) stroke area die and must be replaced by new neurons and proper connections. TGFα infused into the stroke area of striatum, pallidum, and/or cortex, (or intranasally), induces the adult stem cells lining the ependymal and subventricular zone adjacent to the striatum to divide (proliferation) in great numbers (hundreds of thousands to millions of new progenitors) and then migrate to the regions of the striatum, pallidum, and cortex where they differentiate into neurons that have the appropriate brain area markers, whether they be striatal, pallisal, or cortical in nature. The replacement of these new neurons is associated with dramatic improvement in sensorimotor and motor behavior.

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Fluorescence photomontage of a cross section of the left side of a rat’s brain.

The green-labeled cells at right are the new progenitor and adult stem cells that have divided along the ependymal and subventricular zones lining the ventricle adjacent to the striatum, which appears as a black area peppered with clusters of green progenitors migrating toward the stroke lesion at the lower left. The stroke lesion also contains newly formed progenitor cells stained red and green, which have migrated from the subventricular zone at right. Connecting this zone and the site of the healing stroke site is an area of migrating green progenitors. Thus, the adult stem cells migrate from upper right to lower left. TGFα was injected into the brain area overlapping the stroke site.

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Readers may note that intranasal administration of TGFα as described in the Journal of Stroke and Cardiovascular Diseases article demonstrated behavioral recovery of 55%, as opposed to intracranial administration described in the Journal of Neuroscience article which demonstrated 100% recovery. It is the opinion of the authors that this difference in recovery did not result from the method of administration, but rather resulted from the fact that the intracranial administration experiments delivered a significantly higher dosage of TGFa than did the intranasal experiments. It is expected that properly dosed intranasal administration will prove recovery equally efficacious to intracranial administration.

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Pre-migration

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Migration

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